Primary ObjectivesThe current study aims to establish the recommended dose, safety and preliminary efficacy of azacitidine administered IV or SC in children with relapsed/refractory MDS or JMML, in 2 different subgroups (strata) of patients.…
ID
Source
Brief title
Condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The current study aims to establish the recommended dose, safety and
preliminary efficacy of azacitidine administered IV or SC in children with
relapsed/refractory primairy or secondary MDS or JMML, in 2 different subgroups
(strata) of patients.
Secondary outcome
• To determine the safety and tolerability of azacitidine per stratum.
• To determine (preliminary) the hematological remission rate in these patients.
• To describe the durability of response and long-term follow-up, including
that of patients undergoing stem-cell transplant after treatment with
azacitidine.
• To determine the pharmacokinetics of azacitidine in plasma.
• To study the pharmacodynamic effects of azacitidine in pediatric MDS and JMML.
• To describe the number of patients transforming into AML
Background summary
Myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) are
rare malignant diseases of childhood. So far, stem cell transplantation is the
only curative treatment option. No other agents are available to treat these
diseases successfully, and HSCT results in approximately 50% survival only;
hence there is clear unmet medical need. Over the past few years, we have
increasing evidence that aberrant methylation contributes to the malignant
phenotype of JMML and childhood advanced MDS. The demethylating agent
azacitidine has been shown to improve survival in adults with MDS, but so far
no studies are available in children with MDS or JMML. In the current study we
want to establish the recommended dose and preliminary efficacy of azacitidine,
in children with relapsed MDS or JMML in a pre-transplantation window. This
study will provide a preliminary proof of concept whether a demethylating agent
is able to induce responses in these diseases, and whether this agent indeed
results in hypomethylation. Pharmacodynamic studies should provide this proof
of concept.
Study objective
Primary Objectives
The current study aims to establish the recommended dose, safety and
preliminary efficacy of azacitidine administered IV or SC in children with
relapsed/refractory MDS or JMML, in 2 different subgroups (strata) of patients.
Secondary objectives:
• To determine the safety and tolerability of azacitidine per stratum.
• To determine (preliminary) the hematological remission rate in these patients.
• To describe the durability of response and long-term follow-up, including
that of patients undergoing stem-cell transplant after treatment with
azacitidine.
• To determine the pharmacokinetics of azacitidine in plasma.
• To study the pharmacodynamic effects of azacitidine in pediatric MDS and JMML.
• To describe the number of patients transforming into AML
Study design
This is an international, collaborative, prospective, open label, phase I/II
trial. The study will be conducted as an investigator-initiated study in a
European network (EWOG-MDS and ITCC) with Erasmus MC as international sponsor.
Azacitidine will be provided as study medication by Celgene free of charge.
It needs to be mentioned that the HSCT procedure itself is not part of this
protocol and should be performed under EWOG or institutional guidelines at the
discretion of the principle investigator. We will however capture data to
assess whether azacitidine influences outcome post-HSCT.
Intervention
In children older than 1 year of age and a body weight > 10 kg dosing will be
based on BSA, otherwise we will use a mg/kg dose. Three dose levels will be
studied.
Children >1 year of age and >10 kg body weight:
• Level -1 : 50 mg/m2/day IV/SC x 7 days, one course every 28 days
• Level 1: 75 mg/m2/day IV/SC x 7 days, one course every 28 days
• Level 2: 100 mg/m2/day IV/SC x 7 days, one course every 28 days
Children<1 year of age or <10 kg body weight:
• Level -1 : 1,7 mg/kg/day IV/SC x 7 days, one course every 28 days
• Level 1: 2,5 mg/kg/day IV/SC x 7 days, one course every 28 days
• Level 2: 3,3 mg/kg/day IV/SC x 7 days, one course every 28 days
Study burden and risks
Patients will be treated with 3 or more courses of azacitidine, whereas
normally in this situation they would be treated with either supportive care
only or with other chemotherapy. In adults azacytidine is well tolerated, and
this is also expected in children. Pre-treatment before SCT may lead to a
reduced number of relapses post-SCT, which is the long-term goal of this
approach. Vidaza will be given IV to reduce the burden of SC administration,
especially in smaller children. However, when the stability of azacitidine can
not be assured because the administration of azacitidine can not be finished in
45 minutes from time of reconstitution, SC administration should be choosen as
administration method. Each participating center should decide upfront whether
they will choose IV or SC administration of azacitidine.
A central line will be placed, which will also be used for blood sampling.
Procedures will take place under anesthesia or sedation, whichever is more
appropriate.
Wytemaweg 80
Rotterdam 3015 CN
NL
Wytemaweg 80
Rotterdam 3015 CN
NL
Listed location countries
Age
Inclusion criteria
• Diagnosis of relapsed advanced primary MDS or JMML, established at initial
diagnosis by the diagnostic criteria as specified in the EWOG-MDS 2006 protocol
(see appendix 1), and defined as:
o Relapsed MDS:
After a documented CR or PR, this designation is defined as
- a reappearance of blasts in the peripheral blood,
- or >=5% blasts in the bone marrow not attributable to any other cause (e.g.
bone marrow regeneration after consolidation therapy), and confirmed with
flowcytometry.
o Relapsed JMML:
After a documented CR or PR, this designation is defined as
- reappearance of organomegaly
- in combination with elevated WBC with peripheral blood monocytosis (greater
than 1x109/l),
- and/or the reappearance of a cytogenetic or molecular lesion indicative of
prior disease.
- In addition, clinical criteria may be used, which include objective
parameters such as increase in spleen size of >50% from baseline, and/or the
appearance of new skin lesions, and/or oxygen need,
- and/or blast crises/transformation to AML.
• 1 month to <= 18 years old
• Lansky play score >= 60; or Karnofsky performance status >= 60 (appendix 2)
• Life expectancy * 3 months
• Normal renal function defined as less than or equal to NCI-CTCAE grade 1 (max
1.5 x ULN).
• Normal liver function defined as less than or equal to NCI-CTCAE grade 1 (max
2.5 x ULN for transaminases and bilirubin)
• No chemotherapy within 3 weeks of start of study medication. For 6-MP or
low-dose cytarabine in JMML patients 1 week wash-out time is sufficient.
• For JMML patients: saturation >92% without additional supply of oxygen
• For JMML patients: peripheral blood monocyte count greater than 1.0x109/l
• For relapsed patients following HSCT: recovery of all acute toxic effects of
prior chemotherapy/stem-cell transplantation.
• Able to comply with scheduled follow-up and with management of toxicity.
• Reproductive Function
• Female patients of childbearing potential must have a negative urine or serum
pregnancy test confirmed prior to enrollment.
• Female patients with infants must agree not to breastfeed their infants while
on this study.
• Male and female patients of child-bearing potential must agree to use an
highly effective method of contraception approved by the investigator during
the study and for 90 days after the last dose of azacitidine.
• Highly effective methods of contraception include (but not exclusively) the
following contraceptive methods:
• combined (estrogen and progestogen containing) hormonal contraception
associated with inhibition of ovulation
• progestogen-only hormonal contraception associated with inhibition of
ovulation
• intrauterine device (IUD)
• intrauterine hormone-releasing system ( IUS)
• sexual abstinence.
• Written informed consent from patients or from parents or legal guardians for
minor patients, according to local law and regulations.
Exclusion criteria
• Other serious illnesses or medical conditions
• Genetic abnormalities indicative of AML
• JMML patients in whom a diagnosis of Noonan syndrome is suspected based on
clinical history and/or presenting symptoms
• Patients with secondary MDS with underlying bone-marrow failure syndromes
or with familial MDS
• Isolated extramedullary disease
• Symptomatic CNS-involvement
• Current uncontrolled infection
• Cardiac toxicity (shortening fraction below 28%)
• Concurrent treatment with any other anti-cancer therapy is not allowed
• Pregnant or lactating patients
• Patients who cannot be regularly followed up for psychological, social,
familial or geographic reasons
• Patient with expected non-compliance to toxicity management guidelines
• Prior treatment with a demethylating agent
• Allergy to azacitidine or mannitol.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-022235-10-NL |
| CCMO | NL34475.078.11 |